Anxiolytic and Anxiogenic? How the Transcription Factor MEF2 Might Explain the Manifold Behavioral Effects of Oxytocin

The neuromodulator oxytocin, since its first synthesis by du Vigneaud in 1953, has mainly been associated with beneficial physiological effects, as well as positive social and emotional behaviors. This overall positive picture of oxytocin as the "love-, cuddle-, or bonding-hormone" has repeatedly been challenged since then. Oxytocin-induced effects that would be perceived as negative by the individual, such as increased anxiety or potentiation of stress-induced ACTH release, as well as the regulation of negative approach-related emotions, such as envy and schadenfreude (gloating) have been described. The general consent is that oxytocin, instead of acting unidirectional, induces changes in the salience network to shift the emphasis of emotional contexts, and therefore can, e.g., produce both anxiolytic as well as anxiogenic behavioral outcomes. However, the underlying mechanisms leading to alterations in the salience network are still unclear. With the aim to understand the manifold effects of oxytocin on a cellular/molecular level, a set of oxytocin receptor-coupled signaling cascades and downstream effectors regulating transcription and translation has been identified. Those oxytocin-driven effectors, such as MEF2 and CREB, are known modulators of the neuronal and glial cytoarchitecture. We hypothesize that, by determining cellular morphology and connectivity, MEF2 is one of the key factors that might contribute to the diverse behavioral effects of oxytocin

Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair bonding. However, when dysregulated, it is associated with adverse psychiatric traits, such as various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor myocyte enhancer factor 2A (MEF2A) as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A activity as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction

SoFiA: a flexible source finder for 3D spectral line data

We introduce SoFiA, a flexible software application for the detection and parameterization of sources in 3D spectral-line datasets. SoFiA combines for the first time in a single piece of software a set of new source-finding and parameterization algorithms developed on the way to future HI surveys with ASKAP (WALLABY, DINGO) and APERTIF. It is designed to enable the general use of these new algorithms by the community on a broad range of datasets. The key advantages of SoFiA are the ability to: search for line emission on multiple scales to detect 3D sources in a complete and reliable way, taking into account noise level variations and the presence of artefacts in a data cube; estimate the reliability of individual detections; look for signal in arbitrarily large data cubes using a catalogue of 3D coordinates as a prior; provide a wide range of source parameters and output products which facilitate further analysis by the user. We highlight the modularity of SoFiA, which makes it a flexible package allowing users to select and apply only the algorithms useful for their data and science questions. This modularity makes it also possible to easily expand SoFiA in order to include additional methods as they become available. The full SoFiA distribution, including a dedicated graphical user interface, is publicly available for download.Comment: MNRAS, accepted. SoFiA is registered at the Astrophysics Source Code Library with ID ascl:1412.001. Download SoFiA at https://github.com/SoFiA-Admin/SoFi

The Implementation of Preconditioned Epidermal Neural Crest Stem Cells to Combat Ischemic Stroke. Comment on Othman, F.A.; Tan, S.C. Preconditioning Strategies to Enhance Neural Stem Cell-Based Therapy for Ischemic Stroke. <i>Brain Sci. 2020, 10</i>, 893

In the recent review published in Brain Sciences, Othman and Tan suggested several preconditioning strategies to improve stem cell therapy after ischemic brain injury [...

Differential Contribution of Hypothalamic MAPK Activity to Anxiety-Like Behaviour in Virgin and Lactating Rats

The c-Raf – MEK1/2 – ERK1/2 mitogen-activated protein kinase (MAPK) intracellular signalling cascade in neurons plays important roles in the control of a variety of behaviours, including social behaviours and anxiety. These roles partially overlap with those described for oxytocin (OXT), and it has been shown that OXT activates the MAPK pathway in the hypothalamus (of male), and hippocampus (of female) rats. Here, by combining behavioural (light/dark box) and biochemical analyses (western blotting), we tested two hypotheses: (i) that OXT is anxiolytic within the hypothalamus of females, and (ii) that this effect, as well as that of lactation-associated anxiolysis, depends on the recruitment of the MAPK pathway. We found that, when injected bilaterally into the hypothalamic paraventricular nucleus (PVN), OXT decreased anxiety-like behaviour in virgins, and that this effect depended on phosphorylation of MEK1/2. MAPK pathway activation in lactation was evident by high phosphorylated (p) MEK1/2 levels, and nuclear translocation of ERK1. The high pMEK1/2 levels were necessary for the anxiolytic phenotype typically observed during lactation. Interestingly, exogenous OXT in lactating rats reduced pMEK1/2 levels without a concomitant effect on anxiety, indicating that OXT receptor activation can lead to recruitment of additional intracellular pathways to modulate MEK activity. Still other pathways could include MEK, but without subsequent activation of ERK, as we did not observe any increase in OXT-induced ERK phosphorylation. Together the results demonstrate that the MAPK pathway, especially MEK1/2, is critically involved in the regulation of anxiety-like behaviour in female rats

Oxytocin accelerates tight junction formation and impairs cellular migration in 3D spheroids: evidence from Gapmer-induced exon skipping

Oxytocin (OXT) is a neuropeptide that has been associated with neurological diseases like autism, a strong regulating activity on anxiety and stress-related behavior, physiological effects during pregnancy and parenting, and various cellular effects in neoplastic tissue. In this study, we aimed to unravel the underlying mechanism that OXT employs to regulate cell-cell contacts, spheroid formation, and cellular migration in a 3D culture model of human MLS-402 cells. We have generated a labeled OXT receptor (OXTR) overexpressing cell line cultivated in spheroids that were treated with the OXTR agonists OXT, Atosiban, and Thr4-Gly7-oxytocin (TGOT); with or without a pre-treatment of antisense oligos (Gapmers) that induce exon skipping in the human OXTR gene. This exon skipping leads to the exclusion of exon 4 and therefore a receptor that lost its intracellular G-protein-binding domain. Sensitive digital PCR (dPCR) provided us with the means to differentiate between wild type and truncated OXTR in our cellular model. OXTR truncation differentially activated intracellular signaling cascades related to cell-cell attachment and proliferation like Akt, ERK1/2-RSK1/2, HSP27, STAT1/5, and CREB, as assessed by a Kinase Profiler Assay. Digital and transmission electron microscopy revealed increased tight junction formation and well-organized cellular protrusions into an enlarged extracellular space after OXT treatment, resulting in increased cellular survival. In summary, OXT decreases cellular migration but increases cell-cell contacts and therefore improves nutrient supply. These data reveal a novel cellular effect of OXT that might have implications for degenerating CNS diseases and tumor formation in various tissues

The Implementation of Preconditioned Epidermal Neural Crest Stem Cells to Combat Ischemic Stroke. Comment on Othman, F.A.; Tan, S.C. Preconditioning Strategies to Enhance Neural Stem Cell-Based Therapy for Ischemic Stroke. Brain Sci. 2020, 10, 893.

From MDPI via Jisc Publications RouterHistory: accepted 2021-05-13, pub-electronic 2021-05-17Publication status: PublishedIn the recent review published in Brain Sciences, Othman and Tan suggested several preconditioning strategies to improve stem cell therapy after ischemic brain injury [...

The beneficial effects of chick embryo extract preconditioning on hair follicle stem cells: A promising strategy to generate Schwann cells

The beneficial effects of hair follicle stem cells in different animal models of nervous system conditions have been extensively studied. While chick embryo extract (CEE) has been used as a growth medium supplement for these stem cells, this is the first study to show the effect of CEE on them. The rat hair follicle stem cells were isolated and supplemented with 10% fetal bovine serum plus 10% CEE. The migration rate, proliferative capacity and multipotency were evaluated along with morphometric alteration and differentiation direction. The proteome analysis of CEE content identified effective factors of CEE that probably regulate fate and function of stem cells. The CEE enhances the migration rate of stem cells from explanted bulges as well as their proliferation, likely due to activation of AP-1 and translationally controlled tumour protein (TCTP) by thioredoxin found in CEE. The increased length of outgrowth may be the result of cyclic AMP response element binding protein (CREB) phosphorylation triggered by active CamKII contained in CEE. Further, CEE supplementation upregulates the expression of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. The elevated expression of target genes and proteins may be due to CREB, AP-1 and c-Myc activation in these stem cells. Given the increased transcript levels of neurotrophins, VEGF, and the expression of PDGFR-α, S100B, MBP and SOX-10 protein, it is possible that CEE promotes the fate of these stem cells towards Schwann cells

The WiggleZ Dark Energy Survey: Direct constraints on blue galaxy intrinsic alignments at intermediate redshifts

Correlations between the intrinsic shapes of galaxy pairs, and between the intrinsic shapes of galaxies and the large-scale density field, may be induced by tidal fields. These correlations, which have been detected at low redshifts (z<0.35) for bright red galaxies in the Sloan Digital Sky Survey (SDSS), and for which upper limits exist for blue galaxies at z~0.1, provide a window into galaxy formation and evolution, and are also an important contaminant for current and future weak lensing surveys. Measurements of these alignments at intermediate redshifts (z~0.6) that are more relevant for cosmic shear observations are very important for understanding the origin and redshift evolution of these alignments, and for minimising their impact on weak lensing measurements. We present the first such intermediate-redshift measurement for blue galaxies, using galaxy shape measurements from SDSS and spectroscopic redshifts from the WiggleZ Dark Energy Survey. Our null detection allows us to place upper limits on the contamination of weak lensing measurements by blue galaxy intrinsic alignments that, for the first time, do not require significant model-dependent extrapolation from the z~0.1 SDSS observations. Also, combining the SDSS and WiggleZ constraints gives us a long redshift baseline with which to constrain intrinsic alignment models and contamination of the cosmic shear power spectrum. Assuming that the alignments can be explained by linear alignment with the smoothed local density field, we find that a measurement of \sigma_8 in a blue-galaxy dominated, CFHTLS-like survey would be contaminated by at most +/-0.02 (95% confidence level, SDSS and WiggleZ) or +/-0.03 (WiggleZ alone) due to intrinsic alignments. [Abridged]Comment: 18 pages, 12 figures, accepted to MNRAS; v2 has correction to one author's name, NO other changes; v3 has minor changes in explanation and calculations, no significant difference in results or conclusions; v4 has an additional footnote about model interpretation, no changes to data/calculations/result